Although caffeine is the most widely consumed drug in Western society, its precise mechanism of action is still not known. It has been proposed that many or all of its effects are due to antagonism of endogenous adenosine. Although there has been much investigative interest in the effects of adenosine in animals, the cardiovascular clinical pharmacology of adenosine is almost entirely unknown. The proposed studies seek to establish the dose-response relationship for adenosine in human subjects and determine the nature and extent of its shift by concomitantly administered antagonists (caffeine and theophylline) and adenosine uptake blockade (dipyridamole). Clinically, we and others have reported postprandial hypotension in elderly subjects, hypertensive subjects and patients with abnormal autonomic function. We have demonstrated that caffeine attenuates this hypotension and, in normal subjects, caffeine reduces liver blood flow. Since adenosine has been proposed to be an importance regulator of splanchnic blood flow, we propose to evaluate systematically the effect of adenosine infusion, adenosine uptake blockade, and adenosine receptor blockers on liver blood flow and on the hemodynamic response to food ingestion. Studies to determine the relation between the effects of adenosine and caffeine on the one hand and the function of the sympathetic nervous system will also be carried out. These will include assessments of the release and clearance of norepinephrine, measurement of forearm blood flow and venous capacitance, quantitation of sympathetic activity by intraneural recording of sympathetic fibers, and determination of plasma catecholamines, renin and aldosterone. In summary, these studies will elucidate the cardiovascular and autonomic physiology and pharmacology of adenosine.